Antimicrobial Gene Prevents Skin Infection, Offers Alternative to Antibiotic-Resistant Pathogens

Newswise — Bacterial resistance to conventional antibiotics has become increasingly common, resulting in escalating life-threatening infections. In an effort to find an alternative treatment for antibiotic-resistant infections, researchers at the VA San Diego Healthcare System and the University of California, San Diego (UCSD) School of Medicine have shown in human tissue and mice that skin infections can be prevented with the addition of a synthesized version of a pig antimicrobial gene called a cathelicidin. The findings provide a promising alternative to conventional antibiotics.

Published online the week of February 14, 2004 in Proceedings of the National Academy of Sciences, the study showed that the synthesized pig cathelicidin, called PR39, used in combination with natural cathelicidin produced by humans, offered increased protection from an infection by Group A Streptococcus (GAS) when PR39 was delivered to human skin cells in culture. The team also found that when they boosted the volume of the natural single cathelicidin gene in mice, there was no increased resistance to bacteria. However, when the synthesized PR39 pig gene was given to the mice, the researchers saw an increased ability to resist infection.

"While humans and mice have only one cathelicidin gene, domesticated mammals such as the pig and cow have multiple cathelicidin genes," said the study's senior author, Richard L. Gallo, M.D., Ph.D., chief of the UCSD Division of Dermatology (http://medicine.ucsd.edu/derm) and chief of the Dermatology section at the VA Medical Center "We hypothesized that the evolution of multiple cathelicidin genes provides these animals with enhanced resistance to infection, and additional cathelicidins given to humans might fight antibiotic-resistant infections."

In 1994, Gallo was the first to discover antimicrobial peptides " small portions of proteins " in mammalian skin. Subsequent studies by Gallo and others have shown that cathelicidins play a key role in the immune response of the skin and other organs by killing bacteria, viruses and fungi. Recent findings by the Gallo lab have shown that cathelicidins, which are found in various tissues such as skin, lungs, intestines and circulating white blood cells, act as natural antibiotics to provide the body's first line of defense against invading bacteria. In an October 10, 2003 study in the New England Journal of Medicine, Gallo and a team from the National Jewish Medical and Research Center in Denver demonstrated that people with atopic dermatitis " the most common form of eczema " fail to produce cathelicidins that fight infections in other inflammatory skin diseases, such as psoriasis.

Because previous research had indicated that antimicrobial peptides may adversely affect the host, the Gallo team decided to limit activation of the cathelicidins to sites of infection, rather than administer it systemically. While their synthesized PR39 peptide was successful in conferring enhanced resistance against bacterial infection in skin, the team determined that delivery of the native cathelicidin was ineffective in the setting of its natural levels of production. This finding suggested that in normal mice, cathelicidin production was already maximally effective.

According to Gallo, future studies will determine how the cathelicidins therapy would be delivered. It may be as a drug in the form of a cream or ointment, or may be aerosolized, or could be delivered by gene therapy techniques.

The study was funded by the National Institutes of Health and a Veterans Affairs Merit Award to Gallo. The study's co-first authors were Phillip H. A. Lee, M.D. and Takaaki Ohtake, M.D., Ph.D., UCSD/VA post-doctoral fellows. Additional authors were Mohamed Zaiou, Ph.D., Jennifer A. Rudisill, B.S. and Kenneth H. Lin, B.S., UCSD/VA; and Masamoto Murakami, M.D., Ph.D., Asahikawa Medical College, Asahikawa, Japan.

For addition studies by the Gallo team, see:

Peptide Identified as Natural Antibiotic ProvidingFirst Line of Defense Against Bacterial Infectionhttp://health.ucsd.edu/news/2001/11_19_Gallo.html

Lack of Natural 'Antibiotics' in the SkinMay Explain Infections in Dermatitis Patientshttp://health.ucsd.edu/news/2002/10_09_Gallo.html